tbuckley/cabot-search huggingface dataset:
Large-scale analysis of de novo mutations identifies risk genes for female infertility characterized by oocyte and early embryo defects
Authors: Qun Li, Lin Zhao, Yang Zeng, Yanping Kuang, Yichun Guan, Biaobang Chen, Shiru Xu, Bin Tang, Ling Wu, Xiaoyan Mao, Xiaoxi Sun, Juanzi Shi, Peng Xu, Feiyang Diao, Songguo Xue, Shihua Bao, Qingxia Meng, Ping Yuan, Wenjun Wang, Ning Ma, Di Song, Bei Xu, Jie Dong, Jian Mu, Zhihua Zhang, Huizhen Fan, Hao Gu, Qiaoli Li, Lin He, Li Jin, Lei Wang, Qing Sang
Journal: Genome biology (2023)

Abstract Background Oocyte maturation arrest and early embryonic arrest are important reproductive phenotypes resulting in female infertility and cause the recurrent failure of assisted reproductive technology (ART). However, the genetic etiologies of these female infertility-related phenotypes are poorly understood. Previous studies have mainly focused on inherited mutations based on large pedigrees or consanguineous patients. However, the role of de novo mutations (DNMs) in these phenotypes remains to be elucidated. Results To decipher the role of DNMs in ART failure and female infertility with oocyte and embryo defects, we explore the landscape of DNMs in 473 infertile parent–child trios and identify a set of 481 confident DNMs distributed in 474 genes. Gene ontology analysis reveals that the identified genes with DNMs are enriched in signaling pathways associated with female reproductive processes such as meiosis, embryonic development, and reproductive structure development. We perform functional assays on the effects of DNMs in a representative gene Tubulin Alpha 4a ( TUBA4A ), which shows the most significant enrichment of DNMs in the infertile parent–child trios. DNMs in TUBA4A disrupt the normal assembly of the microtubule network in HeLa cells, and microinjection of DNM TUBA4A cRNAs causes abnormalities in mouse oocyte maturation or embryo development, suggesting the pathogenic role of these DNMs in TUBA4A . Conclusions Our findings suggest novel genetic insights that DNMs contribute to female infertility with oocyte and embryo defects. This study also provides potential genetic markers and facilitates the genetic diagnosis of recurrent ART failure and female infertility.
FIPRESCI: droplet microfluidics based combinatorial indexing for massive-scale 5′-end single-cell RNA sequencing
Authors: Yun Li, Zheng Huang, Zhaojun Zhang, Qifei Wang, Fengxian Li, Shufang Wang, Xin Ji, Shaokun Shu, Xiangdong Fang, Lan Jiang
Journal: Genome biology (2023)

Abstract Single-cell RNA sequencing methods focusing on the 5′-end of transcripts can reveal promoter and enhancer activity and efficiently profile immune receptor repertoire. However, ultra-high-throughput 5′-end single-cell RNA sequencing methods have not been described. We introduce FIPRESCI, 5′-end single-cell combinatorial indexing RNA-Seq, enabling massive sample multiplexing and increasing the throughput of the droplet microfluidics system by over tenfold. We demonstrate FIPRESCI enables the generation of approximately 100,000 single-cell transcriptomes from E10.5 whole mouse embryos in a single-channel experiment, and simultaneous identification of subpopulation differences and T cell receptor signatures of peripheral blood T cells from 12 cancer patients.
Programmed Death-Ligand 1 Copy Number Alteration as an Adjunct Biomarker of Response to Immunotherapy in Advanced NSCLC
Authors: Tae Hee Hong, Yeong Hak Bang, Cheol Yong Joe, Soohyun Hwang, Boram Lee, Naeun Lee, Sehhoon Park, Hyun-Ae Jung, Jong-Mu Sun, Jin Seok Ahn, Myung-Ju Ahn, Yoon-La Choi, Se-Hoon Lee
Journal: Journal of Thoracic Oncology (2023)

IntroductionThis study aimed to evaluate the value of programmed death-ligand 1 (PD-L1) copy number (CN) alteration as an additional biomarker to standard immunohistochemistry (IHC) in predicting response to immune checkpoint inhibitor (ICI) therapy in advanced NSCLC.MethodsBefore ICI monotherapy, tumor PD-L1 CN alteration (gain, neutral, or loss) was called using whole-exome sequencing data and compared with IHC results (tumor proportion score ≥50, 1–49, or 0). Progression-free survival (PFS) and overall survival were correlated with both biomarkers. In addition, the impact of CN alteration was further evaluated in two independent cohorts using next-generation sequencing panel.ResultsA total of 291 patients with advanced-stage NSCLC met the study inclusion criteria. Although the IHC classification distinguished the best responsive group (tumor proportion score ≥ 50), the CN-based classification distinguished the worst responsive group (CN loss) from the others (PFS, p = 0.020; overall survival, p = 0.004). After adjusting for IHC results, CN loss was an independent risk factor for progression (adjusted hazard ratio = 1.32, 95% confidence interval: 1.00–1.73, p = 0.049) and death (adjusted hazard ratio = 1.39, 95% confidence interval: 1.05–1.85, p = 0.022). A risk classification system was developed on the basis of IHC and CN profiles, which outperformed the conventional IHC system. In the validation cohorts, CN loss determined by next-generation sequencing panel was independently associated with worse PFS after ICI treatment, revealing its practical value.ConclusionsThis is the first study to directly compare CN alterations with IHC results and survival outcomes after anti–PD-(L)1 therapy. Tumor PD-L1 CN loss can serve as an adjunct biomarker to predict the lack of response. Prospective studies are required to further validate this biomarker.
RecON: Online learning for sensorless freehand 3D ultrasound reconstruction
Authors: Mingyuan Luo, Xin Yang, Hongzhang Wang, Haoran Dou, Xindi Hu, Yuhao Huang, Nishant Ravikumar, Songcheng Xu, Yuanji Zhang, Yi Xiong, Wufeng Xue, Alejandro F. Frangi, Dong Ni, Litao Sun
Journal: Medical Image Analysis (2023)
Pyrazinamide-resistant Tuberculosis Obscured From Common Targeted Molecular Diagnostics
Authors: Samuel J. Modlin, Mikael Mansjö, Jim Werngren, Chidera M. Ejike, Sven E. Hoffner, Faramarz Valafar
Journal: Drug Resistance Updates (2023)

Here, we describe a clinical case of pyrazinamide-resistant (PZA-R) tuberculosis (TB) reported as PZA-susceptible (PZA-S) by common molecular diagnostics. Phenotypic susceptibility testing (pDST) indicated PZA-R TB. Targeted Sanger sequencing reported wild-type PncA, indicating PZA-S TB. Whole Genome Sequencing (WGS) by PacBio and IonTorrent both detected deletion of a large portion of pncA, indicating PZA-R. Importantly, both WGS methods showed deletion of part of the primer region targeted by Sanger sequencing. Repeating Sanger sequencing from a culture in presence of PZA returned no result, revealing that 1) two minority susceptible subpopulations had vanished, 2) the PZA-R majority subpopulation harboring the pncA deletion could not be amplified by Sanger primers, and was thus obscured by amplification process. This case demonstrates how a small susceptible subpopulation can entirely obscure majority resistant populations from targeted molecular diagnostics and falsely imply homogenous susceptibility, leading to incorrect diagnosis. To our knowledge, this is the first report of a minority susceptible subpopulation masking a majority resistant population, causing targeted molecular diagnostics to call false susceptibility. The consequence of such genomic events is not limited to PZA. This phenomenon can impact molecular diagnostics' sensitivity whenever the resistance-conferring mutation is not fully within primer-targeted regions. This can be caused by structural changes of genomic context with phenotypic consequence as we report here, or by uncommon mechanisms of resistance. Such false susceptibility calls promote suboptimal treatment and spread of strains that challenge targeted molecular diagnostics. This motivates development of molecular diagnostics unreliant on primer conservation, and impels frequent WGS surveillance for variants that evade prevailing molecular diagnostics.
TRPC6 inhibitor (BI 764198) to reduce risk and severity of ARDS due to COVID-19: a phase II randomised controlled trial
Authors: Lorraine B Ware, Nima Soleymanlou, Danny Francis McAuley, Vicente Estrada, George A Diaz, Peter Lacamera, Renee Kaste, Wansuk Choi, Abhya Gupta, Tobias Welte
Journal: Thorax (2023)

Background Despite the availability of COVID-19 vaccinations, there remains a need to investigate treatments to reduce the risk or severity of potentially fatal complications of COVID-19, such as acute respiratory distress syndrome (ARDS). This study evaluated the efficacy and safety of the transient receptor potential channel C6 (TRPC6) inhibitor, BI 764198, in reducing the risk and/or severity of ARDS in patients hospitalised for COVID-19 and requiring non-invasive, supplemental oxygen support (oxygen by mask or nasal prongs, oxygen by non-invasive ventilation or high-flow nasal oxygen). Methods Multicentre, double-blind, randomised phase II trial comparing once-daily oral BI 764198 (n=65) with placebo (n=64) for 28 days (+2-month follow-up). Primary endpoint: proportion of patients alive and free of mechanical ventilation at day 29. Secondary endpoints: proportion of patients alive and discharged without oxygen (day 29); occurrence of either in-hospital mortality, intensive care unit admission or mechanical ventilation (day 29); time to first response (clinical improvement/recovery); ventilator-free days (day 29); and mortality (days 15, 29, 60 and 90). Results No difference was observed for the primary endpoint: BI 764198 (83.1%) versus placebo (87.5%) (estimated risk difference –5.39%; 95% CI –16.08 to 5.30; p=0.323). For secondary endpoints, a longer time to first response (rate ratio 0.67; 95% CI 0.46 to 0.99; p=0.045) and longer hospitalisation (+3.41 days; 95% CI 0.49 to 6.34; p=0.023) for BI 764198 versus placebo was observed; no other significant differences were observed. On-treatment adverse events were similar between trial arms and more fatal events were reported for BI 764198 (n=7) versus placebo (n=2). Treatment was stopped early based on an interim observation of a lack of efficacy and an imbalance of fatal events (Data Monitoring Committee recommendation). Conclusions TRPC6 inhibition was not effective in reducing the risk and/or severity of ARDS in patients with COVID-19 requiring non-invasive, supplemental oxygen support. Trial registration number NCT04604184 .
Longevity of centenarians is reflected by the gut microbiome with youth-associated signatures
Authors: Shifu Pang, Xiaodong Chen, Zhilong Lu, Lili Meng, Yu Huang, Xiuqi Yu, Lianfei Huang, Pengpeng Ye, Xiaochun Chen, Jian Liang, Tao Peng, Weifei Luo, Shuai Wang
Journal: Nature Aging (2023)
Intermittent fasting plus early time-restricted eating versus calorie restriction and standard care in adults at risk of type 2 diabetes: a randomized controlled trial
Authors: Xiao Tong Teong, Kai Liu, Andrew D. Vincent, Julien Bensalem, Bo Liu, Kathryn J. Hattersley, Lijun Zhao, Christine Feinle-Bisset, Timothy J. Sargeant, Gary A. Wittert, Amy T. Hutchison, Leonie K. Heilbronn
Journal: Nature Medicine (2023)
IgG:FcγRIIb signals block effector programs of IgE:FcεRI-activated mast cells but spare survival pathways
Authors: Cynthia Kanagaratham, Tahereh Derakhshan, Yasmeen S. El Ansari, Kameryn N. Furiness, Eleanor Hollers, Mats Keldsen, Hans C. Oettgen, Daniel F. Dwyer
Journal: Journal of Allergy and Clinical Immunology (2023)
Genetic susceptibility to diabetic kidney disease is linked to promoter variants of XOR
Authors: Qin Wang, Haiying Qi, Yiming Wu, Liping Yu, Rihab Bouchareb, Shuyu Li, Emelie Lassén, Gabriella Casalena, Krisztian Stadler, Kerstin Ebefors, Zhengzi Yi, Shaolin Shi, Fadi Salem, Ronald Gordon, Lu Lu, Robert W. Williams, Jeremy Duffield, Weijia Zhang, Yuval Itan, Erwin Böttinger, Ilse Daehn
Journal: Nature Metabolism (2023)
Epidemiologic Evaluation of Retinopathy of Prematurity Severity in a Large Telemedicine Program in India Using Artificial Intelligence
Authors: Mallory A. deCampos-Stairiker, Aaron S. Coyner, Aditi Gupta, Minn Oh, Parag K. Shah, Prema Subramanian, Narendran Venkatapathy, Praveer Singh, Jayashree Kalpathy-Cramer, Michael F. Chiang, R. V. Paul Chan, J. Peter Campbell
Journal: Ophthalmology (2023)
Stitching together the emotions of covid
Authors: Alison Shepherd
Journal: BMJ (2023)

A historic artwork in textiles and stitch, recording personal experiences of the pandemic around the world, is to go on public display in London after a tour of UK hospitals.The Covid Chronicle quilt, which measures 36 m by 1 m, is made up of 140 individually embroidered panels submitted by needleworkers from 15 countries.Wendy Bliss, who founded and curated the artistic enterprise, said the individual panels will find a permanent home at the Chelsea and Westminster Hospital in Fulham and West Middlesex University Hospital in Twickenham, "as a mark of thanks to the NHS staff for their personal sacrifices made during the pandemic.
Rapid single-cell physical phenotyping of mechanically dissociated tissue biopsies
Authors: Despina Soteriou, Markéta Kubánková, Christine Schweitzer, Rocío López-Posadas, Rashmita Pradhan, Oana-Maria Thoma, Andrea-Hermina Györfi, Alexandru-Emil Matei, Maximilian Waldner, Jörg H. W. Distler, Stefan Scheuermann, Jens Langejürgen, Markus Eckstein, Regine Schneider-Stock, Raja Atreya, Markus F. Neurath, Arndt Hartmann, Jochen Guck
Journal: Nature Biomedical Engineering (2023)

During surgery, rapid and accurate histopathological diagnosis is essential for clinical decision making. Yet the prevalent method of intra-operative consultation pathology is intensive in time, labour and costs, and requires the expertise of trained pathologists. Here we show that biopsy samples can be analysed within 30 min by sequentially assessing the physical phenotypes of singularized suspended cells dissociated from the tissues. The diagnostic method combines the enzyme-free mechanical dissociation of tissues, real-time deformability cytometry at rates of 100-1,000 cells s-1 and data analysis by unsupervised dimensionality reduction and logistic regression. Physical phenotype parameters extracted from brightfield images of single cells distinguished cell subpopulations in various tissues, enhancing or even substituting measurements of molecular markers. We used the method to quantify the degree of colon inflammation and to accurately discriminate healthy and tumorous tissue in biopsy samples of mouse and human colons. This fast and label-free approach may aid the intra-operative detection of pathological changes in solid biopsies.
Genomic and transcriptomic analysis of checkpoint blockade response in advanced non-small cell lung cancer
Authors: Arvind Ravi, Matthew D. Hellmann, Monica B. Arniella, Mark Holton, Samuel S. Freeman, Vivek Naranbhai, Chip Stewart, Ignaty Leshchiner, Jaegil Kim, Yo Akiyama, Aaron T. Griffin, Natalie I. Vokes, Mustafa Sakhi, Vashine Kamesan, Hira Rizvi, Biagio Ricciuti, Patrick M. Forde, Valsamo Anagnostou, Jonathan W. Riess, Don L. Gibbons, Nathan A. Pennell, Vamsidhar Velcheti, Subba R. Digumarthy, Mari Mino-Kenudson, Andrea Califano, John V. Heymach, Roy S. Herbst, Julie R. Brahmer, Kurt A. Schalper, Victor E. Velculescu, Brian S. Henick, Naiyer Rizvi, Pasi A. Jänne, Mark M. Awad, Andrew Chow, Benjamin D. Greenbaum, Marta Luksza, Alice T. Shaw, Jedd Wolchok, Nir Hacohen, Gad Getz, Justin F. Gainor
Journal: Nature Genetics (2023)

Abstract Anti-PD-1/PD-L1 agents have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC). To expand our understanding of the molecular features underlying response to checkpoint inhibitors in NSCLC, we describe here the first joint analysis of the Stand Up To Cancer-Mark Foundation cohort, a resource of whole exome and/or RNA sequencing from 393 patients with NSCLC treated with anti-PD-(L)1 therapy, along with matched clinical response annotation. We identify a number of associations between molecular features and outcome, including (1) favorable (for example, ATM altered) and unfavorable (for example, TERT amplified) genomic subgroups, (2) a prominent association between expression of inducible components of the immunoproteasome and response and (3) a dedifferentiated tumor-intrinsic subtype with enhanced response to checkpoint blockade. Taken together, results from this cohort demonstrate the complexity of biological determinants underlying immunotherapy outcomes and reinforce the discovery potential of integrative analysis within large, well-curated, cancer-specific cohorts.
Development and validation of DNA methylation scores in two European cohorts augment 10-year risk prediction of type 2 diabetes
Authors: Yipeng Cheng, Danni A. Gadd, Christian Gieger, Karla Monterrubio-Gómez, Yufei Zhang, Imrich Berta, Michael J. Stam, Natalia Szlachetka, Evgenii Lobzaev, Nicola Wrobel, Lee Murphy, Archie Campbell, Cliff Nangle, Rosie M. Walker, Chloe Fawns-Ritchie, Annette Peters, Wolfgang Rathmann, David J. Porteous, Kathryn L. Evans, Andrew M. McIntosh, Timothy I. Cannings, Melanie Waldenberger, Andrea Ganna, Daniel L. McCartney, Catalina A. Vallejos, Riccardo E. Marioni
Journal: Nature Aging (2023)

Type 2 diabetes mellitus (T2D) presents a major health and economic burden that could be alleviated with improved early prediction and intervention. While standard risk factors have shown good predictive performance, we show that the use of blood-based DNA methylation information leads to a significant improvement in the prediction of 10-year T2D incidence risk. Previous studies have been largely constrained by linear assumptions, the use of cytosine–guanine pairs one-at-a-time and binary outcomes. We present a flexible approach (via an R package, MethylPipeR) based on a range of linear and tree-ensemble models that incorporate time-to-event data for prediction. Using the Generation Scotland cohort (training set ncases = 374, ncontrols = 9,461; test set ncases = 252, ncontrols = 4,526) our best-performing model (area under the receiver operating characteristic curve (AUC) = 0.872, area under the precision-recall curve (PRAUC) = 0.302) showed notable improvement in 10-year onset prediction beyond standard risk factors (AUC = 0.839, precision–recall AUC = 0.227). Replication was observed in the German-based KORA study (n = 1,451, ncases = 142, P = 1.6 × 10−5). Early type 2 diabetes (T2D) risk assessment could help slow or prevent disease onset. Here the authors used blood-based DNA methylation data to develop 10-year risk prediction models for incident T2D. The results show an improvement in performance beyond standard risk factors typically used to predict the risk of T2D onset.
Benchmarking: a novel measuring tool for outcome comparisons in surgery
Authors: Yi Wu, Shizhen Li, Jingxiong Yuan, Hang Zhang, Min Wang, Zhenxiong Zhang, Renyi Qin
Journal: International Journal of Surgery (2023)

Introduction: Benchmarking, a novel measuring tool for outcome comparisons, is a recent concept in surgery. The objectives of this review are to examine the concept, definition, and evolution of benchmarking and its application in surgery. Methods: The literature about benchmarking was reviewed through an ever-narrowing search strategy, commencing from the concept, definition, and evolution of benchmarking to the application of benchmarking and experiences of benchmarking in surgery. PubMed, Web of Science, Embase, and Science Direct databases were searched until 20 September 2022, in the English language according to the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. Results: In the first phase of the literature search, the development of benchmarking was identified. The definitions of benchmarking evolved from a surveying term to a novel quality-improvement tool to assess the best achievable results in surgery. In the second phase, a total of 23 studies were identified about benchmarking in surgery, including esophagectomy, hepatic surgery, pancreatic surgery, rectum resection, and bariatric surgery. All studies were multicenter analyses from national, international, or global expert centers. Most studies (87.0%) adopted the definition that benchmark was the 75th percentile of the median values of centers. Performance metrics to define benchmarks were clinically relevant intraoperative and postoperative outcome indicators. Conclusion: Benchmarking in surgery is a novel quality-improvement tool to define and measure the best achievable results, establishing a meaningful reference to evaluate surgical performance.
Circulating fibrocyte percentage and neutrophil-lymphocyte ratio are accurate biomarkers of uncomplicated and complicated appendicitis: a prospective cohort study
Authors: Mohamed Zarog, Peter O’Leary, Miranda Kiernan, Jarlath Bolger, Paul Tibbitts, Stephen Coffey, Gerard Byrnes, Colin Peirce, Colum Dunne, Calvin Coffey
Journal: International Journal of Surgery (2023)

There is increasing evidence that uncomplicated appendicitis (UA) may be treated nonoperatively in cases of UA. This study aimed to evaluate and compare the diagnostic accuracy of circulating fibrocyte percentage (CFP), white blood cell count, C-reactive protein, and neutrophil-lymphocyte ratio (NLR) in diagnosing uncomplicated and complicated appendicitis.Eighty consecutive adult patients presenting with suspected appendicitis were recruited in a cohort-based prospective study between June 2015 and February 2016 at University Hospital Limerick in Ireland. Peripheral venous samples were obtained at the presentation. Clinical, biochemical, radiological, and histopathological parameters were recorded. The CFP was determined by dual-staining for CD45 and collagen-I using flow cytometry analysis and correlated with histopathological diagnoses.Of the 46 patients who underwent appendicectomy, 34 (73.9%) had histologically proven acute appendicitis. A comparison of the diagnostic accuracy of biomarkers demonstrated the CFP had the highest diagnostic accuracy for UA (area under the curve=0.83, sensitivity=72.7%, specificity=83.3%, P=0.002). The NLR had the highest diagnostic accuracy in relation to complicated appendicitis (area under the curve=0.84, sensitivity=75.5%, specificity=83.3%, P=0.005).CFP and NLR are accurate biomarkers of UA and complicated appendicitis.